Type 2 Diabetes (T2D) incidence has been associated with the gene SLC16A11 in large human genetic studies. Research into mechanisms causing this increased risk showed that SLC16A11 alters intracellular protein expression in human hepatocytes resulting changes to fatty acid and lipid profiles when studied ex vivo. Further understanding the effect of genetic variation at SLC16A11 on circulating lipids and metabolites in human whole blood may allow for prevention and earlier treatment of high-risk individuals. We hypothesize that genetic variation in SLC16A11 known to increase T2D risk will also alter metabolite levels in circulating human blood and that these changes might predict intracellular pathways increasing diabetes risk ?occurring both at baseline and after perturbation with nutritional intake or pharmacotherapy. In Specific Aim 1, we will characterize the effect of SLC16A11 risk haplotype on baseline circulating metabolite levels in human whole blood. In Specific Aim 2, we will characterize the effect of SLC16A11 on metabolic response to nutrient intake. We will then test whether a response is nutrient-specific by evaluating circulating metabolite levels after two forms of nutrient intake ? after a glucose load with Oral Glucose Tolerance Test (OGTT) and after a standardized meal with Mixed Meal Tolerance Test (MMTT). In Specific Aim 3, we will characterize how SLC16A11 influences the response to pharmacologic therapy with a commonly-used anti- hyperglycemic agent, metformin. High-risk variation at SLC16A11 will be tested (1) for association with baseline circulating metabolite levels after metformin therapy, and (2) for association with nutrient response after metformin therapy ? using nutritional challenge with both OGTT and MMTT to evaluate for a nutrient specific metformin-related effect. Thus, we will describe how SLC16A11 alters metabolic response to the environment by measuring circulating blood metabolites ? both at baseline and during environmental perturbation with nutrient challenge or pharmacotherapy. These aims reflect a carefully planned training program directed at advancing the scientific career of the applicant. Resources at the Broad Institute and the MGH Center for Genomic Medicine and the mentorship of Jose Florez, a leading expert in the field of diabetes genetics, will allow cutting-edge genomic discovery and advanced metabolomic approaches to be applied to investigate the metabolic effects of the gene SLC16A11 known to be associated with T2D.